Change From Baseline in Weighted Mean Heart Rate 0-4 Hours Post-dose at the End of the 28-day Treatment Period [ Time Frame: Baseline to Day 28 ] [ Designated as safety issue: No ]

Co-Primary Endpoint. Weighted mean was derived by calculating the average area under the curve (AUC), and then dividing by the relevant time interval. Baseline is the most recent result taken on or before pre-dose Day 1. Heart rate was recorded at 60 minutes (min) prior to dosing and at 15 min, 45 min, 90 min, 120 min, and 240 min post-dose on Day 28. Change from Baseline was calculated as the Day 28 value minus the Baseline value. Analysis was performed using a restricted maximum likelihood (REML)-based repeated measures mixed model approach (MMRM) with covariates of Baseline heart rate, sex, age, smoking status, treatment, and day and day by treatment and day by Baseline interactions. par.=participants.

Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) Throughout the Study [ Time Frame: From Baseline (Day 1) until Follow-up (up to Study Day 37) ] [ Designated as safety issue: No ]

Co-Primary Endpoint. An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; or is a congenital anomaly/birth defect. See the SAE/AE module of this results summary for a list of specific SAEs/AEs occurring in the study.

Secondary Outcome Measures:

Mean Change From Baseline in Clinic Visit Trough Forced Expiratory Volume in One Second (FEV1) on Days 2, 15, and 29 [ Time Frame: Baseline; Day 2, Day 15, and Day 29 ] [ Designated as safety issue: No ]

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Days 2, 15, and 29 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Days 1, 14, and 28. The highest of 3 technically acceptable measurements was recorded. Baseline FEV1 is defined as the mean of the two assessments obtained 30 minutes pre-dose and immediately pre-dose on Day 1. Change from Baseline was calculated as the Day 29 value minus the Baseline value. Analysis was performed using Mixed Model Repeated Measures (MMRM) with covariates of Baseline FEV1, sex, age, smoking status, treatment and day, and day by treatment and day by Baseline interactions.

Mean Change From Baseline (Pre-dose on Day 1) in Weighted Mean FEV1 (0-4 Hours Post-dose) on Days 1 and 28 [ Time Frame: Baseline (pre-dose on Day 1); Day 1 and Day 28 ] [ Designated as safety issue: No ]

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Serial FEV1 measurements were taken electronically by spirometry at the Day 1 and Day 28 clinic visits (60 minutes pre-dose; immediately pre-dose; post-dose after 5, 15, and 30 minutes and 1, 2, and 4 hours. Weighted mean was calculated using the 24-hour serial FEV1 measurements that included the 0 to 4 hours post-dose assessment. At each time point, the highest of 3 technically acceptable measurements was recorded. Baseline FEV1 was defined as the mean of the two assessments obtained 30 minutes pre-dose and immediately pre-dose on Day 1. Change from Baseline was calculated as the average Day 28 FEV1 value minus the Baseline value. Analysis was performed using Mixed Model Repeated Measures (MMRM) with covariates of Baseline FEV1, sex, age, smoking status, treatment and day, and day by treatment and day by Baseline interactions.

Post-menopausal females are defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. However if indicated this can be confirmed by estradiol and FSH levels consistent with menopause (according to laboratory ranges) at screening (Visit 1).

Surgically sterile females are defined as those with a documented (medical report verification) hysterectomy and/or bilateral oophorectomy or Tubal Ligation.

Furthermore, male subjects in this study must use double-barrier (condom/spermicide) birth control methods or abstain from sexual intercourse with female partners who are pregnant, lactating, or able to bear children in addition to any birth control methods the female partner is using, from the first dose of the study medication until 90 days after the last dose of the study medication.

COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society [Celli, 2004] :

COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.

Tobacco use: subjects with a current or previous history of ≥ 10 pack-years of cigarette smoking at screening (Visit 1). Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.

• Number of pack years = (number of cigarette per day/20)) x number of years smoked

Severity of Disease: subjects who conform to the current severity classification for Stage II/III disease in terms of post-bronchodilator spirometry at Screening Visit 1:

Chest X-ray (or CT scan): Subjects with a chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at Screening if a chest X-ray or CT scan is not available within 6 months prior to Screening

Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of any of the following in the 6 weeks prior to Screening:

Acute worsening of COPD that is managed by subject with corticosteroids or antibiotics, or

Acute worsening of COPD that requires treatment prescribed by a physician Subjects who are hospitalized due to poorly controlled COPD within 12 weeks of the Screening Visit

Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1

12-lead ECG (Electrocardiogram): An abnormal and clinically significant 12-lead ECG that results in an active medical problem. For this study, an abnormal ECG is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following:

The independent cardiologist, contracted by GSK, will determine the clinical significance of any ECG abnormalities and determine if a subject is precluded from entering the study. However, the following predetermined ECG abnormalities are considered clinically significant and will result in exclusion of a subject:

A mean QTc(B) value at Screening > 450 msec, or uncorrected QT >600 msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T wave)

Other Diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.

Hypertension: Subjects with clinically significant hypertension that is uncontrolled

Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years.

• Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis.

Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications (e.g. beta-agonists, corticosteroid) or components of the inhalation powder (e.g. lactose, magnesium stearate). Or a history of drug or other allergy such as a history of severe milk protein allergy that, in the opinion of the study physician, contraindicates the subject's participation

Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years

Medication prior to spirometry: Subjects who are medically unable to withhold their rescue medication for the 6-hour period required prior to spirometry testing at each study visit.

Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Programme within 4 weeks prior to Screening or who will enter the acute phase of a Pulmonary Rehabilitation Programme during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Programme may be included.

Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures

Questionable validity of Consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study

Prior use of study medication/other investigational drugs: Subjects who have received the GW642444 in previous studies. Subjects who have received an investigational drug within 30 days of entry into this study (Screening), or within 5 drug half-lives of the investigational drug, whichever is longer

Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study

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Please refer to this study by its ClinicalTrials.gov identifier: NCT00731822